How well do you know your mutation? Complex effects of genetic background on expressivity, complementation, and ordering of allelic effects
| Autor: | Kristen Hummel, Michael DeNieu, Christian Marier, Julie Holms, Anna E. Mammel, Christopher H. Chandler, David C. Tack, Leslie Marvin, Cody K. Porter, Ian Dworkin, Sudarshan Chari, Alycia Kowalski, Gayatri Sivaratnam, Anne Sonnenschein, Lin Choi, William Pitchers, Andrew Victory |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Cancer Research Heredity Introgression medicine.disease_cause Genetic analysis 0302 clinical medicine Morphogenesis Drosophila Proteins Wings Animal Genetics (clinical) Genetics 0303 health sciences Mutation biology Gene Expression Regulation Developmental Nuclear Proteins Phenotype Complementation Phenotypes Genetic Mapping Drosophila melanogaster Imaginal Discs Cell Processes Female Genetic Background Research Article Evolutionary Processes lcsh:QH426-470 Genotype Variant Genotypes 03 medical and health sciences medicine Animals Expressivity (genetics) Allele Molecular Biology Gene Alleles Ecology Evolution Behavior and Systematics 030304 developmental biology Cell Proliferation Evolutionary Biology Population Biology Genetic Complementation Test Biology and Life Sciences Epistasis Genetic Cell Biology biology.organism_classification lcsh:Genetics 030104 developmental biology Genetic Loci Genetic Polymorphism Population Genetics 030217 neurology & neurosurgery Transcription Factors Developmental Biology |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 13, Iss 11, p e1007075 (2017) |
| ISSN: | 1553-7404 |
| DOI: | 10.1371/journal.pgen.1007075 |
| Popis: | For a given gene, different mutations influence organismal phenotypes to varying degrees. However, the expressivity of these variants not only depends on the DNA lesion associated with the mutation, but also on factors including the genetic background and rearing environment. The degree to which these factors influence related alleles, genes, or pathways similarly, and whether similar developmental mechanisms underlie variation in the expressivity of a single allele across conditions and among alleles is poorly understood. Besides their fundamental biological significance, these questions have important implications for the interpretation of functional genetic analyses, for example, if these factors alter the ordering of allelic series or patterns of complementation. We examined the impact of genetic background and rearing environment for a series of mutations spanning the range of phenotypic effects for both the scalloped and vestigial genes, which influence wing development in Drosophila melanogaster. Genetic background and rearing environment influenced the phenotypic outcome of mutations, including intra-genic interactions, particularly for mutations of moderate expressivity. We examined whether cellular correlates (such as cell proliferation during development) of these phenotypic effects matched the observed phenotypic outcome. While cell proliferation decreased with mutations of increasingly severe effects, surprisingly it did not co-vary strongly with the degree of background dependence. We discuss these findings and propose a phenomenological model to aid in understanding the biology of genes, and how this influences our interpretation of allelic effects in genetic analysis. Author summary Different mutations in a gene, or in genes with related functions, can have effects of varying severity. Studying sets of mutations and analyzing how they interact are essential components of a geneticist's toolkit. However, the effects caused by a mutation depend not only on the mutation itself, but on additional genetic variation throughout an organism's genome and on the environment that organism has experienced. Therefore, identifying how the genomic and environmental context alter the expression of mutations is critical for making reliable inferences about how genes function. Yet studies on this context dependence have largely been limited to single mutations in single genes. We examined how the genomic and environmental context influence the expression of multiple mutations in two related genes affecting the fruit fly wing. Our results show that the genetic and environmental context generally affect the expression of related mutations in similar ways. However, the interactions between two different mutations in a single gene sometimes depended strongly on context. In addition, cell proliferation in the developing wing and adult wing size were not affected by the genetic and environmental context in similar ways in mutant flies, suggesting that variation in cell growth cannot fully explain how mutations affect wings. Overall, our findings show that context can have a big impact on the interpretation of genetic experiments, including how we draw conclusions about gene function and cause-and-effect relationships. |
| Databáze: | OpenAIRE |
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